Efficacy and Safety of a Single Dose Versus Three Weekly Doses of Benzathine Penicillin G for Early Syphilis: A Systematic Review and Meta-Analysis

Background/Objectives: To compare the efficacy and safety of a single dose versus three weekly doses of benzathine penicillin G (BPG) for the treatment of early syphilis. Methods: We searched Embase, PubMed, and Scopus for randomized controlled trials (RCTs) and prospective comparative studies published in English up to September 2025. The primary outcome was serological cure (≥4-fold decline in non-treponemal titers) at 6–12 months, analyzed on an intention-to-treat (ITT) basis. Risk of bias was assessed using RoB 2 for RCTs and ROBINS-I for non-randomized studies; certainty of evidence was rated with GRADE. Data were synthesized using random-effects meta-analysis and trial sequential analysis (TSA). Results: Three studies (n = 886) met the inclusion criteria. The primary ITT meta-analysis showed no significant difference in serological cure between the three-dose and single-dose regimens (risk ratio [RR] 1.06; 95% CI 0.92–1.21; p = 0.42), with substantial heterogeneity. In an exploratory pre-specified subgroup of patients with high baseline RPR (≥1:32), the three-dose regimen was associated with higher cure rates (RR 1.12; 95% CI 1.02–1.23; p = 0.02; I2 = 0%), but no significant benefit was seen for people with HIV (PWH) (RR 1.08; p = 0.13) or for those with CD4 counts <350 cells/mm3. Risk of bias was serious across all studies, and GRADE certainty was very low for efficacy and low for safety. In a post hoc per-protocol analysis restricted to early latent syphilis, the three-dose regimen yielded higher serological cure (pooled risk difference 12%, 95% CI 1–23; p = 0.03). TSA indicated that the evidence is inconclusive and underpowered. Conclusions: On the basis of the ITT analysis, a single dose of BPG appears to remain effective and safe for most cases of early syphilis, including in PWH, supporting current CDC and WHO recommendations. The apparent advantages of three doses in high-titer and early latent subgroups derive from exploratory and post hoc analyses of studies at high risk of bias with very low certainty of evidence and should be regarded as hypothesis-generating rather than practice-changing. Adequately powered, well-designed trials are needed before any dose stratification can be recommended.